Tau is a microtubule-binding protein that accumulates in a number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease (AD). The presence of abnormal tau correlates with neuron loss and memory deficits in patients with AD and other neurodegenerative disorders that involve tau accumulation. Therefore, selectively reducing tau levels or tau aggregation is an effective therapeutic strategy.
Efforts towards that goal have largely focused on either inhibitors of tau aggregation (see Taniguchi, et al. J Biol Chem, 280:7614 (2005), and Wischik, et al. Proc Natl Acad Sci USA, 93:11213 (1996)), inhibitors of tau phosphorylation (Mazanetz and Fischer, Nat Rev Drug Discov, 6:464 (2007)), or compounds that stimulate tau degradation (Koren, et al., J Cell Mol Med, 13:619 (2009); Jinwal, et al., J Neurosci, 29:12079 (2009); and Oddo, et al., J Neurosci, 28:12163 (2008)). Each of these strategies is potentially promising and well supported by genetic evidence, but many of the compounds identified to date have relatively modest activity. For example, methylene blue (MB), which both inhibits tau aggregation and stimulates tau degradation through heat shock protein 70 (Hsp70), has an EC50 value of approximately 10 μM. Other promising compounds, such as the Hsp90 inhibitors 17-AAG and EC1012, reduce tau levels but they also produce a robust stress response, which is expected to diminish their long-term efficacy.
Neurodegenerative disorders are also associated with expansion of polyCAG tracts (Kaytor et al., J Biol Chem, 274:37507 (1999)). Huntington's disease and several other neurodegenerative disorders are characterized by expansion of a polyglutamine sequence (LaSpada et al., Nature, 352:77 (1991); Koide et al., Nat. Genet., 6:9 (1994)). The expanded polyCAG tracts encode abnormally long polyglutamine sequences within specific proteins promoting their nuclear and/or cytoplasmic aggregation. The protein aggregation is believed to contribute to cellular toxicity including cell death or apoptosis (Trottier et al., Nature, 378:403 (1995); Davies et al., Cell, 90:537 (1997); and DiFiglia et al., Science, 277:1990 (1997)).
MKT-077 is a delocalized lipophilic cationic rhodacyanine (FIG. 1A) that selectively binds Hsp70 in cells, based on biochemical and genetic studies. Recent NMR studies have shown that MKT-077 binds to an allosteric pocket in the nucleotide-binding domain (NBD) of Hsc70, an abundant, cytoplasmic member of the Hsp70 family. This binding site is highly conserved and MKT-077 is active against other family members, such as mitochondrial and prokaryotic Hsp70s. Prior efforts have shown that MKT-077 and its analogs bind Hsp70 family members and have anti-cancer activity in multiple cancer lines, including melanoma cells and carcinomas of the colon, breast and pancreas. Based on these observations, MKT-077 advanced to a Phase I clinical study as an anti-cancer agent. However, progress was halted due to nephrotoxicity in a subset of patients. Renal damage was likely exacerbated by the dramatic accumulation of MKT-077 in the kidney, as shown by whole animal imaging and pharmacodynamic studies. Moreover, these same studies confirmed that MKT-077 does not cross the BBB, blunting any potential use in treating or studying neurodegenerative diseases. Together, these problems have limited use of MKT-077, especially in CNS disorders.
Thus, new compounds that have anti-cancer properties or can regulate tau and/or polyglutamine are of interest.